Over the last year the laboratory has focused on two areas. The first concerns the properties and function of IA-2 and IA-2 which are major autoantigens in type 1 diabetes and transmembrane proteins of dense core secretory vesicles. These proteins are present in most of the neuroendocrine cells in the body. Knockout and knock down technology has shown that these proteins affect the secretion of hormones (e.g., insulin) and neurotransmitters. Current studies are concerned with the effect of IA-2 and IA-2 on the secretion of these hormones and neurotransmitters and how, in turn, they affect a variety of physiologic processes. The second area concerns polyreactive antibodies. Hybridoma technology has shown that many antibody molecules are polyreactive that is, they can bind to a variety of different and structurally unrelated self and non-self foreign antigens. These antibodies generally have low binding affinity and are encoded by germ-line or near germ-line sequences. Further studies revealed that much of the natural antibody repertoire is made up of polyreactive antibody. The function of the natural antibody repertoire has remained an enigma. Current studies are focusing on the role of polyreactive antibodies in: defense against foreign organisms (i.e., bacteria/viruses); the clearance of damaged proteins and cells; and the possible role of these antibodies in the induction and/or maintenance of immunological tolerance. The cells that make polyreactive antibodies also are under investigation.